Proteoglycan Signaling as a New Therapeutic Target for Cocaine Addiction

总结 这个修改后的拨款提案的目标是探索调节大脑活动的策略 蛋白聚糖多配体蛋白聚糖-3用于治疗可卡因滥用。蛋白聚糖如syndecan-3，而 最初被鉴定为细胞外基质（ECM）的组分，也发挥信号传导功能， 生长因子和ECM蛋白的受体和共受体。我们观察到syndecan-3在 外侧下丘脑（LH）在限制强迫性可卡因摄入方面具有意想不到的新作用。 特别地，在特异性目标1中，我们将研究多配体蛋白聚糖-3胞外域脱落和信号转导。 在可卡因摄入调节中的转导。多配体蛋白聚糖-3胞外域的蛋白水解切割，也 在配体相互作用后诱导称为“脱落”的蛋白质，并终止其信号传导。探测 由于胞外域脱落的功能性后果，我们将使用腺相关（AAV）病毒载体来 递送修饰的多配体蛋白聚糖-3构建体，所述多配体蛋白聚糖-3构建体包括抗脱落的多配体蛋白聚糖-3， 单独的胞外域和未修饰的多配体聚糖-3。这些研究的结果将确立 抑制其配体结合胞外域的蛋白水解切割的治疗潜力。研究 特异性目的2将研究多配体蛋白聚糖-3作为GDNF受体的替代物在细胞凋亡能力中的作用。 syndecan-3以减少可卡因自我给药。为此，我们将使用AAV来修改 GDNF构建体被设计为选择性结合多配体蛋白聚糖-3或其典型的高亲和力 GFR-1受体。具体目标2的结果将为未来的研究提供信息， 多配体蛋白聚糖-3及其两个受体系统和信号转导伙伴之间的相互作用， 它的信号活动。 总之，拟议的研究将增加我们对下丘脑功能的理解， 蛋白聚糖syndecan-3作为行为调节剂，并将探索创新的治疗策略， 可卡因滥用的治疗

Summary The goal of this revised grant proposal is to explore strategies to modulate the activity of the brain proteoglycan syndecan-3 for the therapy of cocaine abuse. Proteoglycans like syndecan-3, while originally identified as components of the extracellular matrix (ECM), also play signaling functions as receptors and co-receptors for growth factors and ECM proteins. We observed that syndecan-3 in the lateral hypothalamus (LH) has an unexpected new role in limiting compulsive cocaine intake. In particular, in Specific Aim 1 we will investigate syndecan-3 ectodomain shedding and signal transduction in the regulation of cocaine intake. The proteolytic cleavage of syndecan-3 ectodomain, also known as "shedding" is induced after ligand interaction and terminates its signaling. To probe the functional consequence of ectodomain shedding, we will use adeno-associated (AAV) viral vectors to deliver modified syndecan-3 constructs including a shedding-resistant syndecan-3, the syndecan-3 ectodomain alone, and the unmodified syndecan-3. The results of these studies will establish the therapeutic potential of inhibiting the proteolytic cleavage of its ligand-binding ectodomain. Studies in Specific Aim 2 will investigate the role of syndecan-3 as an alternative GDNF receptor in the ability of syndecan-3 to reduce cocaine self-administration. To this end we will use AAV to transduce modified GDNF constructs designed to bind selectively either to syndecan-3 or to its canonical high-affinity receptor GFR-¿1. The results of Specific Aim 2 will inform future studies aimed at manipulating interactions between syndecan-3 and its two receptor systems and signal transduction partners to boost its signaling activity. Together, the proposed studies will increase our understanding of the functions of the hypothalamic proteoglycan syndecan-3 as a regulator of behavior and will explore innovative therapeutic strategies for the therapy of cocaine abuse.